This invention was in part funded by a grant from Cancer Prevention Research Institute of Texas (Grant number R1009).
Normal cells rely on oxidative phosphorylation for energy production when oxygen is plentiful and anaerobic glycolysis when oxygen is limiting. In contrast, Otto Warburg demonstrated more than 80 years ago that cancer cells have rewired metabolic pathways whereby they primarily rely upon aerobic glycolysis even when oxygen is readily available (the “Warburg Effect”). While research in subsequent years has confirmed and expanded upon Warburg's initial findings, it was largely ignored by cancer researchers. However, the last decade or so has witnessed resurgence in the field of cancer metabolism as it has been recognized as a potential Achilles heel of oncogenesis that may lead to new chemotherapeutics.
The central hypothesis of cancer metabolism is that the seminal oncogenic hallmark of rapid, uncontrolled cellular proliferation requires increased production of energy and biomass in the form of ATP production and lipid synthesis. The increased energy requirements of cancer cells are illustrated by the use of Positron Emission Topography (PET) with 18F-fluorodeoxyglucose (FDG) in cancer patients. Many types of cancer are successfully identified by this FDA-approved technique, which arguably provides some of the strongest support for the central hypothesis that cancer cells have a higher glycolytic demand than normal cells. While many chemotherapeutic agents reduce FDG PET positivity of tumors with some correlation to clinical benefit, the observed reduction in glycolytic flux most likely is secondary to inhibition of cellular proliferation and not a result of directly targeting glycolysis. Researchers have been unsuccessful in directly targeting glycolysis because, even though cancer cells have an acute reliance on this pathway, normal cells also have an absolute requirement for glucose.
At first glance the increased demand for glucose and aerobic glycolysis in cancer cells seems inconsistent because oxidative phosphorylation is a much more efficient use of glucose to produce energy. However, interpreting cancer metabolism only by the quantity of ATP produced is simplistic and may overlook the importance of increased synthesis of macromolecules required for cell division and the links between altered metabolic pathways and oncogenic mutations. Just as cancer cells require more energy to rapidly proliferate, they also require increased biomass. One approach to attack cancer metabolism is to focus on the key cytosolic regulator of lipid, cholesterol and amino acid synthesis, acetyl-CoA. Acetyl-CoA's central role in macromolecule synthesis has been well established, making it an attractive target to disrupt biomass production. Additionally, recent research has shown that acetyl-CoA levels play a pivotal role in acetylation of histones and proteins in yeast and mammalian cells, linking it to epigenetic control of cell growth and proliferation. A novel approach to disrupt acetyl-CoA production is by targeting Acetyl-CoA Synthetase Short Chain 2 (ACSS2). As a primary enzyme responsible for acetyl-CoA generation from acetate, ACSS2 is an ATP-dependent enzyme that catalyzes the transfer of acetate to CoA forming cytosolic acetyl-CoA, which is then converted to lipids, cholesterol and amino acids.
The dependence on acetate by cancer cells can be further demonstrated by 11C-acetate PET imaging. In a manner analogous to FDG PET imaging, 11C-acetate PET has been used successfully to image several tumors in the clinic, thereby demonstrating cancer cells have an increased dependence on acetate. Furthermore, reports have shown a differential preference of acetate or glucose uptake in patient tumors leading to the hypothesis that some cancers preferentially depend on acetate metabolism while others depend on glycolysis.